ORNITHINE DECARBOXYLASE AND ISCHEMIC BRAIN EDEMA

本申请的长期目标是改善治疗， 不完全性脑缺血的基础上，更好地了解 鸟氨酸脱羧酶在缺血性水肿中病理生理作用 发展鸟氨酸脱羧酶（ODC）， 多胺代谢，在发展缺血性脑损伤的脑区增加， 永久性局灶性和短暂性脑缺血后水肿。 免疫组织化学研究将这种增加的ODC活性定位于 神经元细胞体。在缺血前阻断这种酶可以防止 永久性局灶性缺血后血脑屏障（BBB）破坏。 猫永久性局灶性脑缺血模型和短暂性脑缺血模型 沙鼠的脑缺血将用于评估ODC在以下方面的作用： 产生不同的缺血性水肿发展模式， 这两种不同的缺血性损伤重点评估的问题 缺血模型包括：多胺是否介导ODC对 BBB崩溃，如果通过ODC阻断改善BBB完整性的维持 水肿发展，如果ODC阻断导致水肿发展减少 改善缺血后的生理结果，如果开始ODC阻滞， 缺血发作后仍能减轻脑水肿和梗死 发展短暂性脑缺血模型中有待评价的问题 包括：ODC活性增加是否是BBB的原因 崩溃和脑水肿的发展，如果代谢恢复是一个 ODC活性增加的先决条件，如果ODC介导的BBB增加 内皮细胞膜囊泡增加导致通透性增加 运输伊文思蓝外渗，颅内压，特异性 重力和总脑水将用于评估ODC在BBB中的作用 分解和缺血性水肿的发展。病理生理学改变 ODC阻断产生的事件将通过测量梗死 容量、局部脑血流量（氢清除率）和代谢 国家（核磁共振光谱）。完成这些 研究将大大扩展对ODC及其影响的理解 脑缺血后，并将作为可能使用的基础 在临床研究中的ODC阻断。

The long-range objective of this application is to improve therapy for incomplete cerebral ischemia based on a better understanding of the pathophysiological role of ornithine decarboxylase in ischemic edema development. Ornithine decarboxylase (ODC), the ratelimiting enzyme for polyamine metabolism, is increased in brain regions developing ischlmic edema following both permanent focal and transient cerebral ischemia. Immunohistochemistry studies localized this increased ODC activity to neuronal cell bodies. Blockade of this enzyme prior to ischemia prevents blood brain barrier (BBB) breakdown following permanent focal ischemia. Models of permanent focal cerebral ischemia in the cat and transient cerebral ischemia in the gerbil will be used to assess the role of ODC in generating the different patterns of ischemic edema development produced by these two distinct ischemic insults. Questions to be evaluated in the focal ischemia model include: whether or not polyamines mediate ODC's effect on BBB breakdown, if maintenance of BBB integrity by ODC blockade improves edema development, if reduced edema development produced by ODC blockade improves physiologic outcome after ischemia and if ODC blockade started after the onset of ischemia still reduces cerebral edema and infarction development. Questions to be evaluated in the transient ischemia model include: whether or not increased ODC activity is responsible for BBB breakdown and cerebral edema development, if metabolic recovery is a prerequisite for increased ODC activity and if ODCmediated increases in BBB permeability results from increased endothelial cell membrane vesicular transport. Evans blue extravasation, intracranial pressure, specific gravity and total brain water will be used to assess ODC's role in BBB breakdown and ischemic edema development. Alterations in pathophysiological events produced by ODC blockade will be evaluated by measuring infarction volume, regional cerebral blood flow (hydrogen clearance), and metabolic state (nuclear magnetic resonance spectroscopy). Completion of these studies would greatly extend the understanding of ODC and its effects following cerebral ischemia and would serve as a basis for the possible use of ODC blockade in clinical studies.